This mentored research scientist career development award (K01) proposal is a four-year plan to enable the candidate to develop into an independent investigator in the field of psychiatric genetics. This proposal provides for extensive development of his skills in bioinformatics, gene array technology, and SNP-based linkage disequilibrium (LD) studies. These short-term career goals will be accomplished through formal course work, extensive mentorship in a collaborative environment, and implementation of a research plan that will form the basis of a larger body of research aimed at investigating the molecular genetics of bipolar disorder. Mentorship will be provided by Dr. Christopher A. Ross, Director of the Division of Neurobiology in the Department of Psychiatry, and Dr. Melvin G. Mclnnis, Director of the George Browne Genetics Laboratory. Dr. J. Raymond DePaulo, Jr., Director of the Department of Psychiatry will continue to provide expert consultation in clinical practice and psychiatric genetic analysis. Drs. Aravinda Chakravarti, Terri Beaty, Jonathan Pevsner, and Forrest Spencer will provide expert consultation in bioinformatics, LD and microarray analysis. Dr. Francis McMahon, Chief, Genetic Basis of Mood and Anxiety Disorders, NIMH, will provide facilities and assistance in SNP genotyping technology. The didactic training will be complemented by the proposed research project, which is designed to test the hypothesis that gene variations underlie susceptibility to bipolar disorder. This hypothesis has been supported through twin, adoption, and family studies and by recent reports of linkage to a number of regions in the human genome. This project will take advantage of the valuable bipolar disorder family data set that has been compiled under the direction of Dr. DePaulo, and showed strong linkage to the region of 18q21-22. The specific aims are 1). To develop a custom gene array specific to the 18q21-22 region for expression profiling and identification of genes with altered expression and/or splicing variances in BPD; 2). To identify by use of microarray analysis the genes with altered expression in postmortem brain and fresh blood samples from patients with BPD, and to use the more accurate RT-PCR analysis to verify significant findings in array experiments; 3). To identify and genotype SNPs in 18q21-22 in bipolar pedigrees, and to test for allelic or haplotype associations with BPD using LD analysis.